Neuroinflammatory Pathobiology in Gulf War Illness: Characterization with an Animal Model

Principal Investigator: LASLEY, STEPHEN M
Institution Receiving Award: ILLINOIS, UNIVERSITY OF, AT CHICAGO
Program: GWIRP
Proposal Number: GW080150
Award Number: W81XWH-09-2-0098
Funding Mechanism: Investigator-Initiated Research Award
Partnering Awards:
Award Amount: $718,326.00


Many veterans still suffer from Gulf War Illness (GWI) even though it has been many years since they were in the war theater. Our goal is to find out what happened to the troops in the 1991 Gulf War that caused GWI; once we understand the causes, it will help us to find treatments that will work in treating veterans suffering from GWI. We all know how miserable we are when we have a cold or the flu -- we don't want to eat or socialize, we have trouble thinking, our muscles ache, our stomachs might be upset, and we have no energy. Unpleasant as these feeling are, these "sickness" behaviors have a real purpose; they help our body to recover from infection. Our body knows when it is attacked by bacteria and other foreign invaders and responds in a very programmed way; our body detects the invader and releases substances that communicate with the brain and result in behaviors that conserve energy. These inflammatory substances also are released when we get a cut or other type of injury and are an important part of the healing process. As helpful as these chemicals are, they become a problem if the level of them is too high or they stay around too long. You might ask why we are talking about "sickness" behavior when our project concerns GWI. We noticed when veterans with GWI list their symptoms many of them sound like "sickness" behavior. We have an idea (hypothesis) that some of the chemicals that our troops used in the first Gulf War to control insects and keep these pests away from their bodies and the places they lived, as well as the pills they took to guard against possible nerve gas exposure, may be responsible. There is another characteristic of war that may play a role in GWI. Being in a war zone also can be very stressful and the body responds by releasing hormones like cortisol. Short duration exposures to cortisol are not harmful but can be bad if the levels stay high for a long time as they might in a war zone, especially one where troops needed to be extra vigilant about nerve gas attacks. It is possible these chemicals, either alone or along with the stress of the war theater, resulted in "sickness" behavior. Furthermore, we think the brain may have been changed so much by these exposures that a low level of "sickness" behavior continues to this day, and/or the brain "overreacts" to bacterial or other insults so the magnitude or duration of the symptoms of "sickness" behavior are much greater.

Because it is unethical to test our idea by exposing another group of people to chemicals like DEET or the pyridostigmine-containing anti-nerve gas pills, we will test it by exposing mice to these same chemicals. Mice are very useful for this because they show the biochemical aspects of "sickness" behavior much in the say way as humans, so we are confident our research will provide important information about GWI and its treatment. First, we want to know if chemicals the troops were exposed to cause the same brain changes seen with infections. Using mice exposed to a nerve gas-like agent, we already have some data showing that this is the case. By treating mice with a "stress" hormone, we also know that this can make the effects of a nerve agent on the brain worse. Because we can collect brain tissue from the treated mice, we can also say with certainty where in the brain these inflammatory substances do their work. Also, mice have a much shorter lifespan than humans so we can test them for what would be equal to many years in a human's life. In this way we will be able to tell if the brain is changed or supersensitive for a long period after exposure to the Gulf War chemicals. Finally, in previous experiments on other drugs and chemicals toxic to the brain, we have tested the antinflammatory effects of a drug already approved for use in humans. We found that this drug, minocycline, markedly suppresses brain inflammation. We will therefore use this same drug to attempt to suppress brain inflammation caused by exposure to chemicals and the stressful environment of the 1991 Gulf War. Because this drug already is approved for use by the Food and Drug Administration, we hope it can be used very soon for treating GWI if our results in mice show that it works.